Extracellular matrix remodeling upregulates hippocampal neurogenic niche stiffness and impairs neurogenesis in Alzheimer's disease

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Abstract INTRODUCTION Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear. METHODS Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes‐associated protein 1 (YAP1) were achieved using viral vectors. RESULTS We found SGZ stiffening occured early in 3‐month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild‐type mice via supplementing high‐density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase‐1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single‐nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin‐YAP1 mechanotransduction axis played important roles in the stiffness‐induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness‐induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients. DISCUSSION ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro‐neurogenic therapeutics of AD.